Over expression of mutant human amyloid precursor protein (APP) in various transgenic mice leads to several Alzheimer's disease (AD)-type lesions [for reviews see D. Games et al., J Alzheimers Dis 9, 133-49 (2006); J. Gotz et al., Mol Psychiatry 9, 664-83 (2004). These include the development of parenchymal amyloid-beta (Aβ) plaques, neuritic pathology, synaptic loss, and gliosis. A number of reports have shown that active (see D. Schenk et al., Nature 400, 173-7 (1999); D. L. Dickstein et al., Faseb J 20, 426-33 (2006)) and passive (see F. Bard et al., Nat Med 6, 916-9 (2000); M. Buttini et al., J Neurosci 25, 9096-101 (2005); D. M. Wilcock et al, J Neuroinflammation 1, 24 (2004)) Aβ immunotherapeutic approaches are effective in reducing or eliminating these pathologies in preclinical studies (see R. P. Brendza & D. M. Holzman, Alzheimer Dis Assoc Disord 20, 118-23 (2006); C. A. Lernere et al., Rejuvenation Res 9, 77-84 (2006)). In addition, many studies have shown improvement in various cognitive tests (see D. M. Wilcock et al, supra; C. Janus et al., Nature 408, 979-82 (2000); D. Morgan et al., Nature 408, 982-5 (2000)). These findings are supported by mounting correlative findings from both memory testing and neuropathological examination of brains of patients who were enrolled in clinical trials of Aβ immunotherapy (AN1792), see J. A. Nicoll et al., Nat Med 9, 448-52 (2003); I. Ferrer et al., Brain Pathol 14, 11-20 (2004); S. Gilman et al., Neurology 64, 1553-62 (2005).
Recently another common aspect of AD pathology, vascular Aβ (VAβ), has been the subject of scrutiny in preclinical APP transgenic animal studies. In particular, it has been reported that passive immunization has been associated with an increase in VAβ and microhemorrhage (see D. M. Wilcock et al, supra; M. M. Racke et al., J Neurosci 25, 629-36 (2005)). However, predictive clinical implications remain unclear, especially in light of favorable behavioral outcomes in some of these same studies (see D. M. Wilcock et al, supra), the lack of ultrastructural differences in vascular morphology of hemosiderin-positive vessels in untreated and treated transgenic mice (see G. J. Burbach et al., Neurobiol Aging 28, 202-12 (2007)) and, notably, the lack of evidence for significant bleeding or stroke-related consequences in ongoing clinical trials. In addition, little is known about the degree to which VAβ is ultimately affected by Aβ immunotherapeutic approaches; for example, whether outcome measures in chronic treatment paradigms might differ from more acute studies. For instance, it is unknown whether reported increases in VAβ represent a transient phenomenon associated with Aβ clearance, while longer treatment might actually prevent or reverse vascular amyloid. Finally, VAβ effects in transgenic mice may also vary according to the APP mutation employed, since the relative degree of Aβ40 versus Aβ42 production likely influences both the aggregation properties of Aβ as well as the binding efficiency of certain antibodies, particularly those with C-terminal epitopes.